This proposal addresses the molecular control of neuronal cytoskeletal proteins by extracellular signals. The studies proposed here will focus on the regulation and function of the microtubule-associated protein MAP2, a multifunctional neuron-specific protein localized to dendrites. Previous studies under this project established that MAP2 is a multi-functional protein that interacts with both microtubules and actin filaments in a manner regulated by phosphorylation. The continuation of these studies is designed to advance our understanding of MAP2 function by performing detailed analyses of several MAP2-target interactions and their modulation by phosphorylation. High-resolution light microscopy will be used to study the role of MAP2 and its phosphorylated forms in neurite initiation and neuronal growth cone behavior. The mechanism for MAP2's interaction with microtubules and actin filaments will be defined through biochemical analyses. The role of MAP2 as a scaffolding molecule will be examined by combined in vitro and in vivo studies, and novel binding partners for MAP2 will be identified using advanced mass spectroscopy-based approaches. These studies may ultimately identify ways to promote neural regeneration and are fundamentally relevant to several disorders caused by abnormal development or maintenance of neural structure, including mental retardation, neurodegenerative diseases such as Alzheimers, and mental health diseases such as schizophrenia